In these years, we, the present inventors, have paid attention on that some chemical compounds having an aminopeptidase-inhibitory activity exhibit an immunopotentiating activity and an antitumor activity. Recently we have discovered arphamenines A and B and we have found that these arphamenines and some arphamenine-related compounds exhibit physiological activities, including the immunopotentiating activity and the antitumor activity (see Japanese patent application first publication "Kokai" No. 212791/83; pending U.S. patent application Ser. No. 500,396; pending U.S. patent application Ser. No. 619,322 and EPC patent application No. 83105416.8, for example).
Chemical structure of the arphamenine is represented by the following general formula: ##STR2## wherein R is a hydrogen atom or a hydroxyl group. Herein, "arphamenine" is a generic name of arphamenines A and B. The compound of the formula above where R is a hydrogen atom denotes arphamenine A, and the compound of the formula above where R is a hydroxyl group denotes arphamenine B.
On the other hand, we have found that benzylmalic acid having a carboxypeptidase-inhibitory activity shows an immunopotentiating activity ("J. Antibiot.", 37, 682 (1984)).
On the basis of these findings, we have now synthesized a further class of new arphamenine-related compounds represented by the following general formula (I) ##STR3## wherein R.sub.1 denotes a hydrogen atom or an amino-protecting group, R.sub.2 denotes a dimethylpyrimidinyl group, R.sub.3 denotes a hydrogen atom or a hydroxyl group, and R.sub.4 denotes a hydrogen atom or a carboxyl-protecting group. We have now examined these new arphamenine-related compounds for their physiological activities. As a result, it has been confirmed that these new compounds exhibit a carboxypeptidase-inhibitory activity and an immunopotentiating activity. Thus, we have accomplished this invention.
According to a first aspect of this invention, therefore, there is provided as the new compound an arphamenine-related compound represented by the formula (I) ##STR4## wherein R.sub.1 denotes a hydrogen atom or an amino-protecting group, R.sub.2 denotes a dimethylpyrimidinyl group, R.sub.3 denotes a hydrogen atom or a hydroxyl group, and R.sub.4 denotes a hydrogen atom or a carboxyl-protecting group, or a pharmaceutically acceptable salt or ester thereof.
In the formula (I) above, R.sub.1 denotes a hydrogen atom or an amino-protecting group. This amino-protecting group may be an alkoxycarbonyl group such as t-butoxycarbonyl group (usually abbreviated as Boc), an aralkoxycarbonyl group such as benzyloxycarbonyl group (abbreviated as Z) and p-methoxybenzyloxycarbonyl group (abbreviated as Z(OMe)), and an acyl group, including an aliphatic acid residue, for example, an alkanoyl group such as acetyl group, propionyl group and palmityl group etc., and an aroyl group such as benzoyl group.
In the formula (I) above, R.sub.2 denotes such a dimethylpyrimidinyl group as derived from the guanidyl group of arphamenine, especially 4,6-dimethylpyrimidin-2-yl group.
Further, in the formula (I), R.sub.4 denotes a hydrogen atom or a carboxyl-protecting group. The carboxyl-protecting group includes an alkyl group such as methyl group, ethyl group, propyl group and t-butyl group etc.; and an aralkyl group such as benzyl group, p-nitrobenzyl group and p-methoxybenzyl group, and the like.
According to a preferred embodiment of the first aspect invention, there is provided a compound of the formula (I) where R.sub.1 is a hydrogen atom, a benzoyl group or a benzyloxycarbonyl group, R.sub.2 is a 4,6-dimethylpyridine-2-yl group, R.sub.3 is a hydrogen atom or a hydroxyl group, and R.sub.4 is a hydrogen atom.
Particular examples of the compound of the formula (I) are listed below:
Compound No. 1: 5-Benzoylamino-8-[(4,6-dimethylpyrimidin-2-yl)amino]-2-phenylmethyl-4-oxo- octanoic acid. PA0 Compound No. 2: 5-Benzoylamino-8-[(4,6-dimethylpyrimidin-2-yl)amino]-2-(4'-hydroxyphenylme thyl)-4-oxo-octanoic acid. PA0 Compound No. 3: 5-Benzyloxycarbonylamino-8-[(4,6-dimethylpyrimidin-2-yl)amino]-2-phenylmet hyl-4-oxo-octanoic acid. PA0 Compound No. 4: 5-Benzyloxycarbonylamino-8-[(4,6-dimethylpyrimidin-2-yl)amino]-2-(4'-hydro xyphenylmethyl)-4-oxo-octanoic acid.